Amphipathic poly-β-peptides for intracellular protein delivery

Abstract

A series of amphipathic poly-β-peptides are designed and synthesized for intracellular protein delivery. The poly-β-peptides with higher molecular weight and hydrophobic contents exhibit higher protein loading as well as superior...

Intracellular delivery of therapeutic proteins. New advancements and future directions

“…On the other hand, protein-based nanocomplexes can be formed via non-covalent interactions with polymers, functionalized nanoparticles, peptides, and lipids. Amino acid residues may interact via salt bridge, boronate-nitrogen ( Liu X. et al, 2019 ; Liu et al, 2022 ) or metal-nitrogen ( Ren et al, 2022 ) coordination interactions, electrostatic forces ( Rui et al, 2019 ), inter-macromolecular ionic, hydrophobic ( He et al, 2019 ), and hydrogen-bond interactions ( Lv et al, 2020 ). Such assemblies should provide stability during cell membrane penetration and protein release ( Yu et al, 2018 ), via reversible binding ( Stevens et al, 2021 ).…”

“…These nanoparticles can release proteins by intracellular ROS after internalization, with maintained activity and minimal toxicity. Amphipathic poly-b-peptides (Pbps), with designable structures, controllable molecular weights, and proteolysis resistant properties, were also investigated for protein delivery ( Ren et al, 2022 ). Pbps amphipathic and positively charged structures promote non-covalent interactions with proteins and membrane disruption ( Tezgel et al, 2017 ), showing successful delivery of EGFP into osteosarcoma cells.…”

“…In the last years, protein-based therapeutics have gained an increasing interest in all areas of medicine ( Lv et al, 2019 ; Zhang S. et al, 2020 ), attracting the attention of the major pharmaceutical industries ( Ren et al, 2022 ; Pandya and Patravale, 2021 ), due to their remarkable potentials for treatment, diagnosis, and even prevention ( Pakulska et al, 2016 ; Sá et al, 2021 ; Tan et al, 2021 ) of several human pathologies ( Liu et al, 2022 ). Protein therapeutics show notable pharmacological efficacy ( Pakulska et al, 2016 ; Liu X. et al, 2019 ) combined with high therapeutic potency and selectivity with respect to traditional low molecular weight drugs ( Cheng, 2021 ).…”

Facially Amphiphilic Skeleton-Derived Antibacterial Cationic Dendrimers

“…Host defense peptides (HDPs) exert rapid and broad-spectrum antibacterial activity and avoid harming host cells as well as reduce the potential for inducing drug resistance. HDPs tend to segregate a so-called “facially amphiphilic” structure, in which the hydrophilic cationic and hydrophobic residues are facially located on their secondary structures and facilitate the direct membrane disruption of bacteria. − Synthetic polymers have been designed to mimic the activity of HDPs, and one of the most challenging topics is how best to spatially arrange the cationic and hydrophobic residues to form a facially amphiphilic structure within the macromolecular architecture. − Bile acids (BAs), such as cholic acid (CA) and lithocholic acid (LCA), derived from cholesterol in mammals, have a rigid skeleton of four condensed rings and multiple functional groups. − Along with excellent biocompatibility, the hydroxyl groups of CA and polycyclic hydrocarbon structures are located on the α and β surfaces of the rigid skeleton, respectively, and form a rare facially amphiphilic structure similar to HDPs, − promoting a selective localization and penetration into bacterial membranes − and making BAs suitable blocks for designing antimicrobials. ,, In the past decades, by utilizing facially amphiphilic skeletons of BAs, there have been extensive efforts in the development of BA-based antimicrobials in which facially amphiphilic BA skeletons are usually conjugated with some positive segments. − For example, Savage et al − converted the three hydroxyl groups on CA into three flexible primary amine groups . In contrast, to reduce the residual toxicity of small molecules and increase the density of cationic charges, the Tang group , designed a series of antibacterial macromolecules bearing CA quaternary ammonium pendants.…”

Boronate Building Blocks for Intracellular Protein Delivery

“…For example, negatively charged GFP, citraconic acid, and peptides were conjugated on the cargo proteins via biological or chemical methodologies, to enhance their binding affinity with cationic carriers via electrostatic interactions. [41][42][43] Besides, several delivery systems have been reported to deliver native proteins via noncovalent interactions such as electrostatic interactions, [17,44,45] salt bridge, [43,[46][47][48][49] hydrophobic interactions, [50][51][52][53][54] metal-ligand coordinations, [55,56] host-guest interactions, [57] and specific molecular recognition. [58,59] For intracellular protein delivery, there are multiple barriers, including protein binding, cellular uptake, endosomal escape, and protein release, that need to be addressed.…”